Notch is a molecule that contributes to the determination of fate of cells of various tissues, and is indicated to be involved in e.g. differentiation, proliferation, and survival during each stages of early developmental stage, embryonic stage, and after birth. Four types of receptors including Notch1, Notch2, Notch3, and Notch4 as well as five types of ligands including Jagged1, Jagged2, DLL1, DLL3, and DLL4 are reported as the Notch family. When a Notch receptor expressed on an adjacent cell binds with a Notch ligand, the NRR domain present in the lower extracellular domain of the receptor is cleaved by TACE, and due to the structural change of the intracellular domain thus caused, the intracellular domain is cleaved by γ secretase. The Notch Intracellular (NIC) domain formed as a result migrates into the nucleus, forms a heterodimer with transcription factor CSL, and target molecules such as the aHes family or the Hey family are induced and expressed. These downstream molecules further induce and express various genes, and as a result, the Notch signal contributes to e.g. the maintenance of stem cells or progenitor cells, differentiation, cell cycle arrest, and cell fate determination (Non-Patent Literature 1).
Notch is also known to be involved in tumor formation. Notch1 mutation due to t(7; 9) chromosomal translocation was first reported as being related to the onset of pre-T cell acute lymphoblastic leukemia (T-ALL). Moreover, the genome insertion site of Mouse Mammary Tumor Virus (MMTV) which is a spontaneous tumor onset model is reported to be Int3 (Notch4 intracellular domain), and it is reported that epithelial cell cancer such as breast cancer or salivary gland cancer are induced in a transgenic mouse where Int3 was force expressed (Non-Patent Literature 2). Notch4 is also reported to be related to the oncogenesis, progression, or metastasis of breast cancer (Non-Patent Literature 3), melanoma (Non-Patent Literature 4), stomach cancer (Non-Patent Literature 5), B-cell acute lymphocytic leukemia (B-ALL) (Non-Patent Literature 6), chronic lymphocytic leukemia (CLL) (Non-Patent Literature 7), glioma (Non-Patent Literature 8), hepatocellular carcinoma (Non-Patent Literature 9), lung cancer (Non-Patent Literature 10), renal cancer (Non-Patent Literature 11), Kaposi's sarcoma (Non-Patent Literature 12), and the like in humans.
The Notch signal also contributes intratumoral neovascularization. Notch1 and Notch4 are expressed as Notch receptors in vascular endothelial cells, and the expression of DLL4 and Jagged1 are confirmed as ligands. Tip cells present at the tip of new blood vessels highly express DDL4 with VEGF stimulation, and blood vessels are extended by sending a signal to the Notch receptor of the adjacent Stalk cell. On the other hand, Jagged1 competes with DLL4 for the Notch receptor and inhibits the binding of DLL4 with the Notch receptor. Since the signal from Jagged1 is weak compared to that from DLL4, the Notch signal is suppressed by binding with Jagged1. The intensity of the Notch signal is adjusted by the spatially differing expression patterns of these two ligands to control neovascularization (Non-Patent Literature 13).
Production of a DLL4 inhibitory antibody has been reported, in which when the signal from DLL4 is inhibited with a DLL4 inhibitory antibody, immature angiogenesis without bloodstream is enhanced inside a tumor and inhibition of tumor proliferation is induced. This is a completely different phenomenon from when a VEGF inhibitor inhibits the proliferation of vascular endothelial cells to suppress angiogenesis, and the Notch signal is gathering attention as a novel target for neovascularization inhibitors (Non-Patent Literature 14).